EP0779508B1 - Glucose fluorescence monitor and method - Google Patents

Abstract

A glucose monitor, and related method, determines the concentration of glucose in a sample by monitoring fluorescent light produced directly by any glucose present in the sample. The glucose monitor illuminates the sample with ultraviolet excitation light that induces any glucose present in the sample to fluoresce, with the fluorescent light being monitored and processed to determine the concentration of glucose in the sample. A sensor monitors the return light, which includes fluorescent light produced by any glucose in the sample, and generates first and second electrical signals indicative of the intensity of light in two wavelength bands. One wavelength band includes a characteristic spectral peak of glucose fluorescence, and the other wavelength band is a reference band having known spectral characteristics. A processor then processes the first and second electrical signals to determine the concentration of glucose in the sample. A fiber-optic waveguide is used to guide the excitation light from the laser light source to the sample and the return light from the sample to the sensor. The fiber-optic waveguide is housed in a catheter or probe that is adapted to monitor the concentration of glucose percutaneously in the oral cavity tissues of a person's mouth such as the gums. <IMAGE>

Description

This invention relates generally to glucosemonitors and, more particularly, to glucose monitors thatdetermine the concentration of glucose in a sample bymonitoring fluorescent light produced directly by glucose.

Glucose is a basic organic compound found inliving organisms, food, and chemical products, and it isoften advantageous to accurately determine theconcentration of glucose in a sample. For example, aperson having diabetes has lost the ability to produceinsulin that regulates the sugar level in their blood.The affected persons must continually receive insulininjections and must regularly monitor the level of glucosein their blood to regulate the timing of the insulininjections. Glucose monitoring of the blood ordinarilyrequires that a small amount of blood be drawn from thebody. Each time the skin of the body is penetrated todraw the blood, there is a risk of infection in additionto an associated buildup of scar tissue. In addition,considerable time is expended in drawing, processing andtesting the blood.

Typical methods of determining the concentrationof glucose in a sample, such as blood, fall into thecategories of aromatic amine methods, enzymatic methods,oxidation methods, and most recently, infrared reflectionand absorption spectroscopy. Infrared reflection andabsorption spectroscopy in blood generally requiresrelatively complicated and expensive instrumentation andhas limited resolution.

From the discussion above, it should be apparentthat there is a need for a glucose monitor that isrelatively noninvasive, that is simple and rapid to use, and that provides good resolution. The present inventionfulfills these needs.

SUMMARY OF THE INVENTION

The present invention is embodied in a glucosemonitor according to claim 1 and related method according to claim 2 that determines theconcentration of glucose in a sample by monitoringfluorescent light produced directly by any glucose presentin the sample. The glucose monitor illuminates the samplewith excitation light that induces any glucose in thesample to fluoresce, with the fluorescent light beingdetected and processed to determine the concentration ofglucose in the sample.

The glucose monitor according to claim 1 includes a light source, asensor, and a processor. The light source emitsexcitation light that is directed at the sample to induceany glucose in the sample to fluoresce. The excitationlight causes the sample to produce return light, whichincludes fluorescent light produced by any glucose in thesample. The sensor monitors the return light andgenerates two signals representing the intensity of lightwithin two spectral wavelength bands. The first signal isindicative of the intensity of return light having awavelength within a first wavelength band. The secondsignal is indicative of the intensity of light within asecond wavelength band. The processor processes the twoelectrical signals to determine the concentration ofglucose in the sample.

In a more detailed feature of the invention, thelight source emits narrowband light having a wavelengthbetween about 250 nanometers and about 350 nanometers. Atypical narrowband ultraviolet light source is an excimerlaser having a wavelength of 308 nanometers. The firstwavelength band includes a characteristic spectral peak of glucose fluorescence. The peak has a wavelength that isabout 30 to 50 nanometers longer than the wavelength ofthe excitation light. Using an excimer laser, thewavelength of the characteristic spectral peak of glucosefluorescence is between 335 to 355 nanometers. The secondwavelength band is a reference band and is chosen from therange of about 380 to 420 nanometers.

The sensor monitors the return light from thesample. In another more detailed feature of theinvention, the sensor has more than one detector thatsimultaneously monitors the return light within the firstand second wavelength band. In a sensor having twodetectors, one detector determines the intensity of lightwithin the first wavelength band and the other detectordetermines they intensity of light within the secondwavelength band. Each detector provides a signalindicative of the intensity of light within thecorresponding wavelength band.

The processor determines the ratio of the light-intensitiesfor the two wavelength bands from the signals.The concentration of glucose in the sample is determinedfrom the ratio of light intensities.

The sample may consist of a variety ofcompositions and may be of solid or liquid form. Inmonitoring the glucose levels in a person's mouth, thesample is the oral cavity tissues such as the gums or thebase of the tongue.

In another more detailed feature of theinvention, the sensor includes a dichroic filter used toseparate the excitation light from the return light, astop having a slit, and a prism used to separate the turnlight into its spectral wavelengths. The sensor may include a spectrograph having a detector array which isconnected to an optical analyzer.

In another more detailed feature of theinvention, a waveguide is used to guide the excitationlight from the light source to the sample. The same waveguideor another waveguide is used to guide the returnlight from the sample to the sensor. If fiber-optic waveguidesare used, they may be held together in a bundle forease of use.

In another more detailed feature of theinvention, the waveguides are housed in a probe. Theprobe may take many forms depending upon the application.The probe may be a catheter for monitoring theconcentration of glucose in an extra-corporal blood flow.The probe may also be adapted to percutaneously monitorthe concentration of glucose in a person's body throughthe skin such as in the oral cavity tissues of the mouth.

Other features and advantages of the presentinvention should become apparent from the followingdescription of the preferred embodiment, taken inconjunction with the accompanying drawings, whichillustrate, by way of example, the principles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of the glucosemonitoring system embodying the invention.

FIG. 2 is a graph of the intensity of glucosefluorescence versus wavelength when a glucose sample isilluminated with laser light having a wavelength of 308nanometers.

FIG. 3 is a graph of the intensity of plasmafluorescence versus wavelength when a human plasma sampleis illuminated with laser light having a wavelength of 308nanometers.

FIG. 4 is a graph of the concentration ofglucose versus the ratio of the intensity of light in awavelength band characteristic of glucose fluorescence tothe intensity of light in a reference wavelength band.

FIG. 5 is a block diagram of a first embodimentof a glucose monitoring system using fiber-opticwaveguides.

FIG. 6 is a block diagram of a second embodimentof a glucose monitoring system using a fiber-opticwaveguide, which simultaneously carries excitation lightto the sample and response light from the sample.

FIG. 7 illustrates a fiber-optic catheter foruse in monitoring the concentration of glucose in a bloodflow.

FIG. 8 illustrates a fiber-optic probe for usein monitoring the concentration of glucose in a personpercutaneously.

FIG. 9 illustrates a fiber-optic probe for usein monitoring the concentration of glucose percutaneouslyin the oral cavity tissues of a person's mouth such as thegums.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in the exemplary drawings, the presentinvention is embodied in a glucose monitoring system 10for determining the concentration of glucose in asample 12 by monitoring the fluorescence of glucosedirectly, without the use of fluorescent dyes or the useof other indirect methods. Also, the glucose fluorescencemonitoring system uses relatively inexpensiveinstrumentation and provides better resolution than prioroptical spectroscopy methods. The glucose fluorescencemonitoring system is relatively noninvasive, givesimmediate results and is easily adapted to most laboratoryand clinical units. The monitoring system does notrequire drawing blood from the body since it can monitorthe glucose concentration percutaneously thus eliminatingthe related blood processing techniques such ascentrifugation, storing and other time consuming testing.

In the glucose monitoring system 10 shown inFIG. 1, alight source 14 directsultraviolet excitationlight 16 at thesample 12, to induce any glucose withinthe sample to fluoresce. Asensor 18 monitors returnlight 20 from the sample, such return light includingglucose fluorescence, and generates two electricalsignals corresponding to the intensity of return lightwithin two predetermined wavelength bands. The firstelectrical signal represents the intensity of return lightwithin a wavelength band that includes a characteristicspectral peak of glucose fluorescence. The secondelectrical signal represents the intensity of return lightwithin a reference wavelength band. The first and secondelectrical signals are communicated from the sensor to aprocesser 22 onlines 24 and 26, respectively. Theprocessor then processes the two electrical signals todetermine the concentration of glucose in the sample.

Thelight source 14 is also referred to as theexcitation source. Theexcitation light 16 from the lightsource can have a wavelength from 250 nm to 350 nm. Theexcitation light can be produced from any type of narrowbandultraviolet light source. In the preferred embodiment, the light source is an ultraviolet excimer laserhaving a wavelength of 308 nm and an energy density of 12millijoules per square millimeter. Alternatively, anitrogen laser, an optically-chopped helium-cadmium laser,a frequency-multiplied diode laser, or a solid-state lasercan be used. The intensity or energy density of theexcitation light should exceed one millijoule per squaremillimeter but should not exceed 15 millijoules per squaremillimeter. If the energy density is too high, ablationof the sample can occur, whereas if the energy density istoo low, obtaining a sufficient electrical signal can bedifficult.

The detectors in thesensor 18 can be as simpleas individual light-sensitive diodes, with appropriatebandpass filters, or as complicated as an opticalmultichannel analyzer that analyzes a broad spectrum ofthe return light. Preferably, a simple CCD array is usedto monitor a variety of wavelengths as desired with eachindividual cell monitoring a specific wavelength region.

In its simplest form, theprocessor 22 receivesthe electrical signals from thesensor 18 and almostinstantaneously provides a ratio of the signals. Theprocessor can further process the ratio to determine andindicate the presence, absence, or concentration ofglucose in thesample 12.

The process of determining of the concentrationof glucose in the sample is better understood withreference to FIGS. 2-4. The spectrum shown in FIG. 2 isthe fluorescence spectrum of glucose after excitation withan ultraviolet excimer laser light having a wavelength of308 nanometers. The spectrum is shown to have a doublepeak that is characteristic of all glucose solutions. Onespectral peak corresponds to a broad fluorescence bandcentered at approximately 440 nanometers, and the other spectral peak corresponds to anarrow fluorescence band 30centered at approximately 345 nanometers. The wavelengthof the peak of the narrow fluorescence band isapproximately 30 to 50 nanometers longer than thewavelength of the excitation light. The narrow glucosefluorescence band is the characteristic wavelength band ofglucose that is monitored to determine the concentrationof glucose in the sample.

As shown in FIG. 3, the fluorescence spectrum ofhuman plasma, when excited by ultraviolet excimer laserlight having a wavelength of 308 nanometers, is distinctfrom the fluorescence spectrum of glucose. Thefluorescence spectrum of human plasma has abroadfluorescence band 32 centered at approximately 380nanometers and anarrow fluorescence band 34 centered atapproximately 345 nanometers. Thenarrow fluorescenceband 34 corresponds to thenarrow fluorescence band 30 ofglucose fluorescence and is indicated by a small peakhaving a wavelength that is approximately 30 nanometersshorter than the wavelength of the larger peak of thebroad fluorescence band 32 of human plasma. Thenarrowfluorescence band 34 is the characteristic wavelengthband of glucose fluorescence that is monitored todetermine the concentration of glucose in the sample. Thereference band is chosen from a wavelength band that isdistinct from thenarrow fluorescence band 34 of glucosefluorescence.

As disclosed in FIG. 4, the glucoseconcentration Cgl in the sample is determined from theratio of measured light intensities within the desiredwavelength bands (Igl/Iref). The first light intensityIgl represents the intensity of light measured within afirst wavelength band corresponding to thecharacteristicwavelength band 34 of glucose fluorescence disclosed inFIG. 3. The second light intensity Iref represents intensity of light measured within a second wavelengthband corresponding to the reference wavelength band. Whenusing an excimer laser, the first wavelength band extendsfrom about 335 nanometers to about 355 nanometers and thesecond wavelength band extends from about 380 nanometersto about 420 nanometers, or some portion thereof. Theratio Igl/Iref increases with increasing glucoseconcentration in the sample. The exact relationshipbetween the glucose concentration and the intensity ratiois empirically derived.

FIG. 5 shows a first embodiment, in which theconcentration of glucose in thesample 12 is determined byilluminating the sample and by capturing the resultingfluorescence spectrum using fiber-optic waveguides, 36 and38. A first fiber-optic waveguide 36 guides the laser orexcitation light 16 from theexcitation source 14 to thesample. The excitation light is collimated when it isemitted from the excitation source.and is directed towardthe fiber using amirror 40 that is highly reflective toultraviolet light having a wavelength of 308 nanometers.The excitation light is focused into the first fiber-opticwaveguide using alens 42. The excitation light travelsalong the first fiber-optic waveguide to the sample.

Theexcitation light 16 causes thesample 12 toproduce scatteredreturn light 20 having a spectrum thatdepends upon the composition of the sample. The returnlight includes any reflected excitation light and thefluorescent light produced by the sample includingfluorescent light produced by any glucose present in thesample. The return light is collected by a second fiber-opticwaveguide 38 and is guided to and emitted unfocusedtowards the entrance of aspectrograph 44. At theentrance of the spectrograph is a long pass filter (notshown) having a cutoff wavelength of about 335 nanometerswhich excludes from the return light any reflected excitation light. Also at the entrance of thespectrograph is a slit having a width of 100 micrometers.The slit is followed by a diffraction grating having 150grates per millimeter and a prism (not shown) thatresolves the return light along an axis. A position alongthe axis corresponds to a wavelength of the return light.

Along the axis is positioned adetector 46,preferably a 1024-element charge-coupled device array.Each element of the detector array corresponds to aspectral wavelength of the return light. The detectorarray provides ananalog signal 48 that is converted intoa digital signal for determination of the concentration ofglucose in thesample 12. The digital signal containsdata representing the intensity of light received for eachof the spectral wavelengths. The data may also bedisplayed on the screen of an optical-multichannelanalyzer 50 or saved on a data disk. In the preferredembodiment, the detector is a 1024 element charge-coupleddevice array, part number EG&G 1422G.

The concentration of glucose in thesample 12 iscalculated from the ratio of the light intensity collectedin two spectral wavelength bands or regions. Using thedata from the detector array, the intensity of lightwithin the first wavelength band is compared with theintensity of light from the second wavelength band.

A related embodiment is shown in FIG. 6. Thisembodiment uses a single fiber-optic waveguide 52 totransmit theexcitation light 16 to thesample 12 and tocollect the return light 20 from the sample. A firstlens 42' focuses the excitation light into the end of thefiber-optic waveguide 52 and also collimates the collectedreturn light that is emitted from the fiber-opticwaveguide. The collimated return light passes through theultraviolet mirror 40 and through a long passoptical filter 54. The long pass optical filter has a cutoffwavelength of 335 nanometers to filter reflectedexcitation light from the return light. The fluorescentlight is focused into another fiber-optic waveguide by asecond lens 56. This second fiber-optic waveguide 58transmits the return light to the entrance of aspectrograph. As discussed above, the spectrographresolves the fluorescent light into its individualspectral components which are analyzed to determine theconcentration of glucose in the sample.

In yet another embodiment shown in FIG 7, thewaveguide is contained within acatheter 60. The cathetermay contain one fused silica fiber or a bundle of manyfibers. The catheter can be indwelling for use in an on-linemonitoring system. It may also sense the glucose inan extra-corporeal blood flood, such as in a heart-lungmachine or in a dialysis system.

Alternative embodiments of thecatheter 60 areshown in FIGS. 8 and 9. In FIG. 8, the catheter 60' isshown to monitor the glucose of ahuman body 62percutaneously, or through the skin. In FIG. 9, thefiber-optic catheter 60" preferably is used topercutaneously monitor the glucose concentration in theoral cavity tissues of a person's mouth, such as thegums 64 or at the base of the tongue. Thus the glucoseconcentration in the human body can be monitored throughthis relatively noninvasive approach that uses ultravioletfluorescence spectroscopy.

The glucose fluorescence monitoring system 10functions with other bodily fluids as well as with solidorgans. It is also applicable to a broad range of glucosesensing needs in food processes such as bread making, winemaking and soft drink manufacturing. The glucose concentrationwithin many translucent or transparent bodies can be monitored. Also, all kinds of biological and non-biologicalfluids can be monitored including plasma,urine, soda, food products, wine, etc.

From the foregoing, it will be appreciated thatthe concentration of glucose in a human body can bemonitored without requiring blood to be drawn from thebody. The glucose monitor monitors the fluorescence ofthe glucose directly giving a direct determination of theglucose concentration. The fiber-optic waveguides simplifythe delivery of the excitation light to the sample andthe collection of the return light from the sample. Theglucose monitor provides almost instantaneous monitoringof the glucose concentration.

Although the foregoing discloses preferredembodiments of the present invention, it is understoodthat those skilled in the art may make various changes tothe preferred embodiments shown without departing from thescope of the invention. The invention is defined only bythe following claims.

Claims (3)

1. Apparatus for determining the concentrationof glucose in a sample, comprising:

   a light source that emits excitation lightthat is directed at a sample to produce return light fromthe sample, such return light including fluorescent lightproduced by any glucose present in the sample;

   a sensor that monitors the return light andgenerates a glucose fluorescence signal indicative of theintensity of return light within a wavelength bandassociated with the direct fluorescence of glucose andgenerates a reference signal indicative of the intensityof return light within a reference wavelength band; and

   a processor that processes the glucosefluorescence signal and the reference signal to determinethe concentration of glucose in the sample.
2. A method of determining the concentrationof glucose in a sample, comprising:

   directing excitation light at a sample tocause the sample to produce return light, such returnlight including fluorescent light produced by any glucosepresent in the sample;

   monitoring the return light and generatingfirst and -second signals, the first signal indicative ofthe intensity of the return light within a firstwavelength band and the second signal indicative of theintensity of return light within a second wavelength band;and

   processing the first and second signals todetermine the concentration of glucose in the sample.
3. A method according to claim 2,futher comprising:

   directing excitation light at a sample tocause the sample to produce return light, such returnlight including fluorescent light produced by any glucosepresent in the sample;

   monitoring the return light and generatingglucose fluorescence signal and a reference signal, theglucose fluorescence signal indicative of the intensity ofthe return light within a wavelength band associated withthe direct fluorescence of glucose and the referencesignal indicative of the intensity of return light withina reference wavelength band; and

   processing the glucose fluorescence signaland the reference signal to determine the concentration ofglucose in the sample.

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